Maoecrystal Z

A busy couple of weeks in the Reisman lab, it appears – really nice syntheses of the Cepharatines and 8-Demethoxyrunanine in Angewandte (doi: 10.1002/anie.201104487), but I decided to blog this tasty synthesis of Maoecrystal Z. Of course, this isn’t the first member of that family that I’e blogged – the seminal synthesis of Maoecrystal V made my December 2010 column in Chemistry World. I remember when I wrote that piece that the pseudo-3D structure used to represent the target annoyed me – in far too many papers, the author uses such a structure when a normal 2D sketch would do. However, trying to ‘flatten’ Maoecrystal Z or it’s family members is an exercise in mental self-harm – the best I could do is shown below, and is frankly ugly.

So what’ll do is stick to Reisman’s figures and hope that you can follow along…

The synthesis starts with γ-cyclogeraniol, initially TBS protecting the primary alcohol, and then epoxidising the exo-cyclic alkene using mCPBA. This takes them to the substrate for a rather ‘witches-brew’ type reaction, coupling the epoxide with methyl acrylate. The conditions were inherited from Gansauer, first published in his 1998 paper on reductive epoxide couplings (look at the hyperlink to see a reminder that Wiley used to be crap with DOI codes!), requiring the zinc as the terminal reductant. Unfortunately, the initial results were relatively poor – only a 28% yield was possible. However, by moving to 2,2,2-trifluoroethylacrylate rather than methyl acrylate, and adjusting the rate of addition of catalyst, the group were able to boost this to a very respectable 74%. Especially nice when you consider how direct this reaction is!

Working directly from the product of that reaction, the group coupled on a sidechain by alkylation, and added a pair of stereocenters. One came with the sidechain, and was it’s self constructed using a pseudo-ephidrine controlled alkylation (and I’ve got a feeling I’ve made this substrate myself, many years ago…). The other wasn’t controlled, and was later removed by oxidation of the lactone to an α,β-unsaturated lactone using the tried-and-tested phenyl-selenation and oxidising elimination.

After this, it was time to move to the pièce de résistance, a samarium (II) iodide mediated radical coupling. Treating the advanced intermediate with SmI2 initially resulted in disappointment, as only trace quantities of the product were identified. However, utilising lithium chloride and tert-butanol as additives saved the day, allowing the group a very reasonable 45% yield, with cracking stereoselectivity.

Bouyed with this success, the group then went made a similar substrate, but this time with an aldehyde instead of the protected primary alcohol. When this substrate was treated in the same manner, not only did a further ring formation occur, but the yield was improved to an even more impressive 54%.

More importantly, though – this pair of C-C bond formations and ring formations took the group remarkably close to the target in a single step. From here, the acetate group (actually, two…) was installed, followed by ozonolysis and treatment of the aldehyde with Eschenmoser’s salt and triethylamine to get to an enal. They the (slightly) selectively removed the erroneous actetate, completing the target in twelve steps.

Judging by the SI (don’t have access to the main paper) the enantiomer shown for the I-containing intermediate was used to make the test compound for the SmI2 coupling but the opposite enantiomer was used in the actual synthesis.
The figure for the test coupling is missing a methylene (at the OTBS) in the starting material & intermediate.
To make a better 2D representation of maoecrystal Z rotate the left ring 30 degrees counterclockwise, shift the lactone slightly down & to the left, & either tilt the OH to the right so it is in front of the O-CO bond or move it inside the 5-membered ring.
The Greek letters aren’t displaying for me either.

The opposite enantiomer was used to decrease the step count. Desilylation-oxidation on the diOTBS gives the dialdehyde.
With the original enantiomer (model study), after the olefin is oxidized to the the aldehyde, you are left with selective desilylation of the diOTBS.

The Nobel committee has made it clear that organic synthesis and especially total synthesis is not really science, but rather a service industry to provide tools for biologists and pharmacologists. This is why Nobels in chemistry always go to biochemists and why organic jobs are so easily sent overseas. Don’t you think that you guys should spend your time a little more wisely by studying medchem or re-training in another field? The funding organizations all agree that this stuff is a waste of time and resources.

Actually, there have been more Nobel laureates in the organic field than in any other field of chemistry. But arguably only two of these were in the discipline of natural product synthesis, and these are widely seen as “lifetime achievement” awards.

Why should I care what the Swedish academy of sciences thinks of the field in which I work if 1) I enjoy what I do, 2) am able to make molecules of interest to many fields, 3) discover useful methodology en-route to said molecules. Since most good and great scientists will never win a Nobel prize anyway, why dwell on it? Med chemists (ADMET is a dead giveaway) need the tools we develop, unless you are satisfied mucking around for months with some reaction a good synthetic chemist could do in a weekend because of the training they received working on complex molecules.

At my company, if we need a library of compounds for screening, we send the chemistry off to our indian CRO and let them worry about the trivial little details of the synthesis. When we receive the compounds, we screen them, look at the data and then the real science begins that leads to drugs that will help people. The synthesis is just turning the crank.

So you think that the situation where the only the synthesis is out-sourced is sustainable? I really don’t think so. The CRO chemists working in India are clearly doing a pretty good job – certainly very cost effective. So how long until until the scale-up is out-sourced too? And the compound design? How long until all that is left in the West is a marketing outfit? That’s certainly a model that Pfizer would like, and one that AstraZeneca might be forced to adopt.

Next, how damn smart and scientific is your lead-optimisation route? Because many of the smartest mind on the block learnt that skill through Total Synthesis. Just ask Tony Wood.

Going back to your outsourced compound series, how many of those compounds have any real structural diversity? Or are all put together with reductive amination, Suzuki couplings and amino alkylations? I’ll go ahead and make the assumption that we’re talking about a couple of hundred compounds at a time, swapping hetero-atom positions around a hetercyclic ring, and perhaps doing the methyl, ethyl, propyl, futile business as usual. So what’s so damn smart about the design process? Isn’t it a bit embarrassing that we haven’t really got a better model for lead identification than just doing a fairly dumb process of sticking everything we’ve got against the target in-vitro? Sure, we’ve got to a point where we can do that unthinking thing really really quickly, and with some amazing bits of kit, but it’s not a smarter process, is it?

And remind me – when did a Med Chemist last win a nobel prize?

Now I’ll mediate my own comment – I worked as a Med Chemist for nearly three years for a subsidiary of a Big Pharma outfit. And I really enjoyed it. I found the science exceptionally interesting, the people endlessly enthusiastic and engaging, and the work exciting. But I think the industry (in the West at least) is going down the pan die to mismanagement at the board level. No one is truly accountable for projects, and the quotas required (i.e. each section to get two CDs per year, or one phase 2a) mean that any old shit will get punted across the line by group-thinking execs. So I’m out…

@ Tot. Syn, thank-you for producing a much more articulate response to a troll than I was able to. The total synthesis people will inherit the earth. You could argue that Sir James Black, Nobel, 1988 was the last Nobel laureate who worked in the field of med-chem, but probably at a higher level of thought than Sir. ADMET.

Certainly, CRO’s in India are doing some custom synthesis for you and they are taking care of trivial details (which for some reason you cannot!!). We send out work (including some biology/biochemistry) to Indian companies too and the reason is they are now much more sophisticited in that job than many other options in the west or the east. As a result the science done in India is been encouraged and so is the academic funding (has gone up 4 four fold from 2005 and counting). So clearly, in the near future they will be competing force in academic field and I think that will be a revival of synthetic chemistry and total synthesis. And sometime soon they will be doing the non-trivial work of ‘looking and the data’ that leads to help people.Actually, to the best of my knowledge they already are!!!

And just to add a bit more of facts, they are now taking over CRO units in the west (e.g Chirotech, Cambridge), so as to reap the scientific expertise here and thats very clever and nice of them…say thank you!

It is exactly this type of narrowmindedness that is at the root of many problems with pharmaceutical industry today. There will never be any innovation through an approach based on avoiding solving complex problems. Good luck in finding (or keeping) a job, let alone coming up with an innovative drug.

To begin, (CJ) trolls live under bridges and I live in a huge house in connecticut because I earn six figures in Pharma. So get back into your fume hood CJ.

One little tip for all of you academics living in your ivory towers: big complex molecules do NOT make good orally bioavailable drugs. Have you ever heard of Lipinski’s Rules? Look it up kids. Oh, and by the way, manipulation of an Accord or Excel spreadsheet is a highly valued job skill in Pharma. If you organic chemists had that skillset, then you’d be suitable to be my secretary instead of a cashier at Target.

@ Sir ADMET
I learned about Lipinski’s rules when I was an undergrad. It was the sort of thing that we learned early on because it was pretty easy to understand. Learning about the subtle nature of stereocontrol and reactivity had to wait until I got more intellectual maturity, which is something you appear to lack….

I synthesize topologically complex marine natural products. You have probablly even heard of a molecule I made with my own hands, if you read the literature. Many complex natural products are indeed bioaviable orally, have you ever heard of seafood poisoning?

Connecticut, that is the state to the south of me. Are you at Groton? Word on the street is that site isn’t doing so hot. I heard all the folks who are going to advance in their careers will be moving to Cambridge. However, associates such as yourself will probablly stay down there until your spreadsheet crunching gets outsourced to India. I know what is up, you don’t. I don’t normally respond to trolls, but I had a few beers tonight and my inhibitions are lowered, and I thought I would fire back, because I have no scruples about sinking to your level. You will be obsolete some day, and I will not be, because intelligence never goes out of style. So how do you like them apples?

Hmm… Lipinski’s rules are more guidelines, though, aren’t they? How many of the top ten selling drugs actually fit the ‘rules’?Fluticasone is a steroidal natural product derivative (do you get irony?)’ and definitely doesn’t fit Lipinski, but is the second best selling drug last year! Paclitaxel hardly fits- and is mostly natural product. Etanercept is a ‘Biologic’ with a MW of 51k… And so is Infliximab at a whopping 144k. And Rituximab, and Darbepoetin alfa… Back into ‘small molecule’ territory, and Montelukast has a MW of 580ish, so that doesn’t fit…

So the rules are really just a way of filtering-out ideas, and heading towards a stereotypical drug. But doesnt that limit the creativity of the Medicinal Chemist? As I said before diversity is important – and not just because it opens up new IP areas…

Tot. Syn.:
Etanercept and Infliximab must be reconstituted with a diluent and then injected subcutaneously! Thank you for proving my point about the oral bioavailability potential of complex natural products! Son, leave the drug development business to the experts in Pharma and stick to blogging about academic silliness.

What’s your point? Both have astonishing sales, so who cares about the bioavailability? If you think your CEO is interested in your bioavailabilty, you should deimmerse yourself from your fog of Excel. Way to dodge the discussion.

As for my ‘academic silliness’, I’m quite happy with my 71,200 visits from 21,000 unique visitors per month (as well as writing a monthly opinion piece in Chemistry World, and reviewing for Nature Chemistry). If ‘SpeedyGonzales’ is right, and you are working at Groton, I think you should be a lot more worried about your own career. After all, that purchase of Wyeth has worked out event worse that of Pharmacia. (Almost) closing Sandwich is an appalling move – can you justify that in any sense?

If you like those two drugs (Etanercept and Infliximab) so much then perhaps your blog should be entitled ‘biosynthetic fermentation of pharmaceutically-relevant biologic agents’ because there was NO total synthesis involved in the development of either of those products. It is certain, however, that spreadsheet manipulation was utilized in bringing those products to market. Stop disparaging the good people in Groton and come out of the ivory towers of stereocontrol and join the Pharma experts in the real world where we help people by providing life-saving drugs.

So your idea of the drugs of the future are ones without topological complexity that do not require the knowledge of stereocontrol to synthesize? Well, sounds like you’re stuck in the past. Computer modelling is only going to get better and better, and more sophisticated ligands for proteins will require more sophisticated chemistry to develop. Maybe with all of your excel smarts you can be my secretary someday.

You dismiss our efforts by waving protein-based drugs in front of us? We put our sweat and blood to discover and optimise drugs… life-saving… depends on context, and even then there are plenty of drugs of each type that can be labelled as “life-saving” drugs. Aren’t we already helping? You think you can make your drugs without the entire team of people in the lab (buying out not counted)? Oh sure you might get away without (med) chemists for all your antibodies… then in that case I’d like to see you not take pills at all. Perhaps you might want to re-evaluate what is called “real science”, or start appreciating the people who (can) deal with “the trivial little details of synthesis”, even if they’re oceans apart.

Look who’s in the real world. And look who’s in an ivory tower. Oh by the way, ivory towers are fragile.

Sad, isn’t it, that a fellow in a huge house in Connecticut earning 6 figures has nothing more constructive to do with his time and infinite wisdom than to provoke people anonymously over the web. The internet is such a wonderful place.

Well, this has been a really entertaining Andy Kaufman bit. Thanks to ‘Totally Synthetic’ for serving as my Jerry ‘the King’ Lawler and thanks to the organic chemistry community for being my professional wrestling fans. This has been fun.

I want to give some credit to SpeedyGonzales for having a couple of beers and standing up for what he believes in. Today’s organic chemists really need to be ambassadors for this field and show this kind of courage more often, even if they are studying their way to an uncertain economic future (the same way that I did). We are tragically lacking a Carl Sagan that can convince American hillbillies that we deserve to have funding. And I’m talking about funding for Phil Baran-esque ‘protecting group-free make me a gram of biologically useless palau’amine just because it has a catchy name.’ Otherwise, China and India will do this sort of work and the outstanding Chinese and Indian chemists that emerge will build Chinese and Indian companies and America will continue its painful decline. Bummer. Good luck kids.

Hahaha! You’ve revealed your bias/nationality ADMET. Are you a bitter Asian or Indian? You are obviously not American, and if you are, you are the worst type (self-loathing American). You can deny whatever you like because the fact remains you are a coward. Spit your vitriol into the silent void…no one can attack you back. How many outstanding Chinese and Indian chemists exist as compared to European/US chemist? Did you check the massive number of retracted papers from these groups lately? They are mind-boggling. How about the NaH oxidation?? Ha!

As you are obviously narcissistic, I get the feeling that you have a very low self esteem (like all narcissists). In this instance, the way around your inner self-loathing is to attack a field of science in which you obviously do not understand in order to make you feel superior in whatever respect you feel you are lacking. Maybe you need laid, or a shrink, I don’t know….but you really have too much times on your hands

This is why I hate Facebook. The same childish ranting is acceptable because you are not face to face with anyone but a computer screen. Like the guy in the car who gives the finger to a pedestrian, and then speeds away if the pedestrian runs up to the car for a confrontation.

I wonder why if you are in the know, why don’t you run your own company? Take the s**t to china so you can earn 5 figures best if your such a genius.

This is ADMETguy. I’m writing from my huge desk located in my huge house in connecticut because I’m employed in the Pharma Industry. Listen: I know how hard it is when you’re stuck in the middle of a crappy synthesis Ph.D. project and you’re not sure if you’re even good enough to finish it. And even if you do, your future consists of moving back in with mommy and daddy because there are no jobs for you. I get that. So I know where your angst is coming from. Additionally, I realize that you’re introverted, and so you’re having a hard time making friends on Facebook and probably you’re not very good at Farmville either.

But…I have to caution you about your racist comments against the Chinese. Some of my best friends in Pharma are Chinamen and they are NOT going to appreciate your anti-Asian tone. There are plenty of outstanding papers from China that haven’t been retracted yet. So ease up on the Chinese. If you stay in chemistry, you’ll probably need to move there someday.

Finally, I don’t need laid at all. The pharmaceutical company that pays my huge salary just hired Bengu Sezen and I’ve been banging her for the last month. So life is pretty good here. As for you, I’ve heard that James J. La Clair is still single. I have his mobile number if you’re interested. Get back in the fume hood, son.

Oh, and if synthesis is easily outsourceable and thus dead, then what the hell is banging mindlessly on a keyboard (to “design” drugs) and shipping jobs elsewhere? (Or you’re living in The Diamond Age, in which case you’re also expendable.) Unless you’ve got friends on your board of directors or dirty pictures of upper management, India’s already trained a generation of computer people who can do your job, and I’m sure that there’ll be another generation of people elsewhere who figure (with good reason) that they can run projects better than you. If they can’t do it better than you, well, they’ll be out of business shortly.

KT and K-Y (K-Y, i won’t even comment on your nickname):
Don’t be so sensitive. There is more to life than undergrad classes classes at your women’s college. By the way, nobody in Pharma cares about the synthesis of Maocrystal Z. It is an enal and anyone who is a big deal in Pharma, such as myself, knows that that is a toxicophoric fragment and this compound could never be a drug.

Hap:
Stop giving handjobs to your boy at In The Pipeline. By the way, Derek, like myself, works in Pharma and hates total synthesis too. He’s constantly making fun of KC Nicolaou for coloring his six-membered rings purple in his Angewandte abstracts. I happen to love KC’s colorful abstracts. I shows his sense of style. And you have to have an impeccable sense of style to be a huge deal in Pharma like I am.

They had to pay me to bang ADMETguy. Considering how poorly equipped he is. But at least he has a nice house and a lot of money. I haven’t seen his car yet, but I’m sure it also compensates quite nicely.

Benju, my love, my equipment issues were supposed to remain confidential! Now, you’ve gone and shared it with all 10 of the graduate students who follow this blog! Such a betrayal…I really thought that your ethical code made you perfectly suited for a high-level position in Pharma. But now it seems that it may not work out between the two of us.

I was told about this thread by a coworker, and started salivating for a fight. Suffice it to say I was a little bit disappointed to find that you guys are all relatively reasonable (except at the end there), and the exchange seemed to have let slip a little of the ‘ivory tower’ academic tension with ‘outsource ’til we die’ industry.

I understand that this site’s small-molecule orientation will skew its audience toward pharma, but I think that we synthesis jocks put our blinders on too tightly sometimes. We do not live and die with the pharmaceutical industry. And it’s certainly true that those of us who are graduating with PhD’s in hand and total syntheses under our belts are finding that the entry-level stateside pharma jobs have been trimmed down from their early-aught luxuries or have vanished altogether (note to ADMETguy: probably a sensitive subject to mention on a site with a very large grad student following. if you were in fact trying to prove a point, you could do it a lot better than by pissing in everyone’s cheerios before making it).

But, the bright side is, at the end of the day, we make shit. And that shit includes high tech polymers, small molecule pharmaceutical agents, and many of the cutting edge applied stuff that the world is going to need (at a consistent level of proprietary demand) for the next 100 years. We can always come back and read totsyn to keep current. But we should all ask ourselves if we chose to learn synthesis simply to become drug mules for a multinational company? Or did we want to do the most refined and creative construction work that the world has ever seen, and apply it to the most pressing problems we face as a global society?

I do know this- the chemical industry is practically salivating at the synthetic talent that’s slipping through pharma’s fingers. I’ve had a number of conversations with a higher-up at a major chemical company, and he’s amazed that the quality of synthetic organic talent that’s suddenly available to companies that have been overlooked for the past 20 years. So, to pharma, I say it’s your loss. To the rest of us- stop bitching; let’s break new ground.

I couldn’t agree more. I now work as Project Leader (and Lab Manager for 14 chemists) for a huge chemical company (AkzoNobel), and have great career prospects. I’m about to turn 31, and am quite glad I left Pharma. We’ve been recruiting chemists like nobodies business – the group I work in now totalled about 20 this time last year, but it now close to 70. And there are plenty of organic chemists in the team.

One brief comment on being compared with Patrick Bateman:
My ripped up physique makes Patrick Bateman look like Rich Taylor. Secondly, Patrick Bateman is a soulless egomaniacal psychopath and I happen to be a Project Leader in Pharma. Ummm…well, OK, I guess I see the similarities there. But my abs are way better than his! Enough of this nonsense! My CRO in Bangalore has finally delivered on a library of ninth-generation PDE5 inhibitors so I am up to my ears in Excel Spreadsheet data that I need to sort and color code. In other words, It’s time to go and save some lives kids! To the 8 graduate students that are currently reading this, Get back into your fume hoods ladies!

For >98% of the academics, this statement says it all. Yes, you are correct, you make shit. Shit nobody cares that it took 65 steps and 0.008% yield. Bravo for pointing this out.

And, I doubt you’ll get too many buyers on most blogs regarding the salivating that going on in the chemical industry. Or, better yet, salivating is all that is going on. Those chemical companies with 1% R&D budget will be hiring <1 chemist per year.

Congrats on the new gig. You won’t have the opportunity to save lives everyday like I do in Pharma, but hey, we all have to work. By the way, if your company ever needs any topologically complex paints, you should think about recruiting SpeedyGonzalez. I hear that he is very good.

I will pay someone else to make my paint when I am earning 5 figures each time I consult with the fine folks in Pharma on how to deal with molecules that have more than a couple of stereocentres. Most pigments contain flat conjugated chromophores, much like those libraries that the CROs are making for number crunchers like you. Sounds like when you are unemployed in a couple of years, and have to sell your big fancy house in Connecticut that the pigment industry might be good for you. You already seem to like colours.

You may have money ADMET, but judging by the content of your posts you clearly have no intellect. Grow up child. Why would you be on here acting silly if you really were this rich and successful pharma team leader? You’d be enjoying your life with all this money you supposedly have and not give a damn about organic chemists and their careers, right? And of course you wouldnt be wasting your precious time on totallysynthetic cause you wouldnt give a damn and have no interest in the subject, right?
Your claims sound like BS to me.